A viable model of bone cancer has been developed in which lytic sarcoma cells are injected into the intramedullary space of the mouse femur. The cells are confined within the bone by an amalgam plug produce extensive bone destruction and pain behaviors similar to that observed in patients with bone cancer. A breast cancer cell line bone pain model will also be developed. With these models the cellular and neurochemical pathophysiology that generates and maintains cancer-induced bone pain can be studied. These studies are proposed to define the distribution and time course of tumor invasion in bone, tumor angiogenesis, osteoclast proliferation, bone destruction, remodeling and bone cancer nociceptive behaviors (Aim 1). The studies will define sensory and sympathetic innervation of bone as the interosseus mass grows and nociceptive state changes assessing tumor growth and bone destruction (Aim 2). Neurochemical changes in the spinal cord, dorsal column nuclei, and sympathetic and dorsal root ganglia will be monitored (Aim 3). Pharmacological manipulation of the generation and maintenance of bone cancer nociceptive events will be attempted (Aim 4). The information generated by these studies should significantly expand our understanding of the cellular and molecular mechanisms involved in the generation of bone cancer pain and may lead to effective therapies for treating bone cancer pain.